U.S. patent number 6,884,905 [Application Number 10/374,508] was granted by the patent office on 2005-04-26 for degradable carbamate-containing bis(acryloyl) crosslinkers, and degradable crosslinked hydrogels comprising them.
This patent grant is currently assigned to Biosphere Medical. Invention is credited to Alexander Schwarz, Hongmin Zhang.
United States Patent |
6,884,905 |
Zhang , et al. |
April 26, 2005 |
Degradable carbamate-containing bis(acryloyl) crosslinkers, and
degradable crosslinked hydrogels comprising them
Abstract
One aspect of the present invention relates to base-labile,
carbamate-containing crosslinkers. A second aspect of the present
invention relates to degradable crosslinked polymers and hydrogels
comprising a base-labile, carbamate-containing crosslinker. The
present invention also relates to methods of preparing base-labile,
carbamate-containing crosslinkers. Another aspect of the present
invention relates to methods of preparing cross-linked polymers and
hydrogels comprising a base-labile, carbamate-containing
crosslinker.
Inventors: |
Zhang; Hongmin (Duxbury,
MA), Schwarz; Alexander (Brookline, MA) |
Assignee: |
Biosphere Medical (Rockland,
MA)
|
Family
ID: |
31191022 |
Appl.
No.: |
10/374,508 |
Filed: |
February 25, 2003 |
Current U.S.
Class: |
560/158 |
Current CPC
Class: |
C07C
271/60 (20130101); C08F 222/385 (20130101) |
Current International
Class: |
C07C
271/00 (20060101); C07C 271/60 (20060101); C08F
222/00 (20060101); C08F 222/38 (20060101); C07C
271/00 () |
Field of
Search: |
;560/158 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO 01/44307 |
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Jun 2001 |
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WO |
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WO 01/68720 |
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Sep 2001 |
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WO |
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WO 01/68722 |
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Sep 2001 |
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WO |
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Other References
Argade et al.; "Preparation and Characterization of Novel
Biodegradable tri-and tetraacrylate Intermediates", Polymer
Bulletin 31: 401-407, (1993). .
Bruining et al.; "Biodegradable Three-Dimensional Networks of
Poly(dimethylamino ethyl methacrylate). Synthesis, Characterization
and in Vitro Studies of Structural Degradation and Cytotoxicity",
Biomaterials 21: 595-604, (2000). .
Bruining et al.; "New Biodegradable Networks of
Poly(N-vinylpyrrolidinone) Designed for controlled Nonburst
Degradation in the Vitrreous Body", J Biomed. Mater. Res.
47:189-197, (1999). .
Eo, Akala; "Hydrolysis of Linear Copolymers with Pendant N,
O-diacylhydroxylamine Moieties)", Pharm. Pharmacol. Lett. 8(3):
129-132, (1998). .
Grosse-Sommer and Prud'homme; "Degradable Phosphazene-crosslinked
Hydrogels", Journal of Controlled Release 40: 261-267, (1996).
.
Gombotz and Petit; "Biodegradable Polymers for Protein and Peptide
Drug Delivery", Bioconjugate Chem. 6: 332-351,(1995). .
Ruckenstein and Zhang; "A Novel Breakable Cross-Linker and
pH-Responsive Star-Shaped and Gel Polymers", Macromelecules 32:
3979-3983, (1999). .
Sawhney et al.; "Bioerodible Hydrogels Based on Photopolymerized
Poly(ethylene glycol)-co-poly(.alpha.hydroxy acid) diacrylate
Macromers", Macromolecules 26: 581-587, (1993). .
Ulbrich et al.; "Synthesis Of Novel Hydrolytically degradable
Hydrogels for Controlled Drug Release", Journal of Controlled
Release 34: 155-165, (1995). .
Ulbrich et al.; "Novel Biodegrdable Hydrogels Prepared Using the
divinyl;ic Crosslinking Agent N, O-dimethacryloydroxylamine. l.
Synthesis and Characterization of Rates of Gel Degradation, and
Rate of Release of Model Drugs, in Vitro and Vivo", Journal of
controlled Release 24: 181-19, (1993)..
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Primary Examiner: Zucker; Paul A.
Attorney, Agent or Firm: Gordon; Dana M. Foley Hoag LLP
Parent Case Text
RELATED APPLICATIONS
This application claims the benefit of the filing date of U.S.
Provisional Patent Application Ser. No. 60/397,909, filed Jul. 23,
2002.
Claims
We claim:
1. A compound represented by 1: ##STR23##
wherein X represents independently for each occurrence O or S; L
represents independently for each occurrence --O--NH--Q; Q
represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--; R represents
independently for each occurrence H or alkyl; Z represents
--NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--; Ar represents independently for each
occurrence aryl or heteroaryl; J represents independently for each
occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2
O).sub.n, or (CH.sub.2 CH.sub.2 N(R)).sub.n ; n represents
independently for each occurrence an integer in the range 1-10; and
m represents independently for each occurrence an integer in the
range 0-10.
2. The compound of claim 1, wherein X represents O.
3. The compound of claim 1, wherein Q represents acryloyl, or
2-methacryloyl.
4. The compound of claim 1, wherein R represents H.
5. The compound of claim 1, wherein Z represents
--NH(CR.sub.2).sub.n NH--.
6. The compound of claim 1, wherein X represents O; and L
represents --O--NH--Q.
7. The compound of claim 1, wherein X represents O; L represents
--O--NH--Q; and Q represents acryloyl, or 2-methacryloyl.
8. The compound of claim 1, wherein X represents O; L represents
--O--NH--Q; Q represents acryloyl, or 2-methacryloyl; and R
represents H.
9. The compound of claim 1, wherein X represents O; L represents
--O--NH--Q; Q represents acryloyl, or 2-methacryloyl; R represents
H; and Z represents --NH(CR.sub.2).sub.n NH--.
10. A compound represented by 2: ##STR24##
wherein X represents independently for each occurrence O or S; M
represents independently for each occurrence --O--NH--Q; Q
represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--; R represents
independently for each occurrence H or alkyl; Z represents
--NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--; Ar represents independently for each
occurrence aryl or heteroaryl; J represents independently for each
occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2
O).sub.n, or (CH.sub.2 CH.sub.2 N(R)).sub.n ; G represents
(CR.sub.(4-t)), aryl, or heteroaryl; n represents independently for
each occurrence an integer in the range 1-10; m represents
independently for each occurrence an integer in the range 0-10; and
t represents 3 or 4.
11. The compound of claim 10, wherein X represents O.
12. The compound of claim 10, wherein Q represents acryloyl, or
2-methacryloyl.
13. The compound of claim 10, wherein R represents H.
14. The compound of claim 10, wherein X represents O; and M
represents --O--NH--Q.
15. The compound of claim 10, wherein X represents O; M represents
--O--NH--Q; and Q represents acryloyl, or 2-methacryloyl.
16. The compound of claim 10, wherein X represents O; M represents
--O--NH--Q; Q represents acryloyl, or 2-methacryloyl; and R
represents H.
17. A method of preparing a compound represented by 1:
##STR25##
wherein X represents independently for each occurrence O or S; L
represents independently for each occurrence --O--NH--Q; Q
represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.N C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--; R represents
independently for each occurrence H or alkyl; Z represents
--NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--; Ar represents independently for each
occurrence aryl or heteroaryl; J represents independently for each
occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2
O).sub.n, or (CH.sub.2 CH.sub.2 N(R)).sub.n ; n represents
independently for each occurrence an integer in the range 1-10; and
m represents independently for each occurrence an integer in the
range 0-10. (a) reacting a hydroxylamine with an acrylate, thereby
forming an acrylic hydroxamic acid; and (b) reacting said acrylic
hydroxamic acid with a diisocyanate.
18. A method of preparing a compound represented by 2:
##STR26##
wherein X represents independently for each occurrence O or S; M
represents independently for each occurrence --O--NH--Q; Q
represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--; R represents
independently for each occurrence H or alkyl; Z represents
--NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--; Ar represents independently for each
occurrence aryl or heteroaryl; J represents independently for each
occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2
O).sub.n, or (CH.sub.2 CH.sub.2 N(R)).sub.n ; G represents
(CR.sub.(4-t)), aryl, or heteroaryl; n represents independently for
each occurrence an integer in the range 1-10; m represents
independently for each occurrence an integer in the range 0-10; and
t represents 3 or 4;
comprising: (a) reacting a hydroxylamine with an acrylate, thereby
forming a hydroxamic acid; and (b) reacting said hydroxamic acid
with a triisocyanate or tetraisocyanate.
Description
BACKGROUND OF THE INVENTION
Biocompatible polymeric materials have been used extensively in
medical implant devices. For some applications (e.g., bone
fixtures, sutures, drug containing implants etc.), the polymers
should be not only biocompatible, but also degradable into
non-toxic products. This degradability eliminates the need to
remove later the device from the implant site.
The first degradable polymers were based on hydrophobic polymers
like PLGA, poly(orthoesters), polyanhydrides and
polyiminocarbonates, which degrade hydrolytically into
water-soluble monomers and oligomers. The degradation times of
these polymers are a function of their chemical composition. The
problem with these polymers is the need to keep them completely dry
during storage. Additionally, the majority of degradable polymers
are essentially hard, brittle materials, developed for drug
delivery uses.
Other degradable polymers are based on naturally-occurring
polymers, e.g., polysaccharides or polypeptides. The degradation
process is based on enzymatic hydrolysis of the polysaccharides or
polypeptides. While these products can be formed as hydrogels, and
therefore may be stored in an aqueous environment, the degradation
time is not controllable due to variable enzyme expression in
humans. Additionally, only the unmodified part of the protein or
polysaccharide is degradable, while modified sites are not
degradable. Furthermore, naturally-derived products have to undergo
vigorous testing to ensure that they are free of endotoxins and
contaminating proteins. For human- or animal-derived proteins,
viral contamination is a constant worry.
Another approach to degradability is to synthesize a hydrogel
containing an unstable crosslinker. This approach has been
investigated by a number of groups. The first approach was to
polymerize the hydrogel in situ using photopolymerization of
monomers that contain a hydrolytically labile lactic acid
component. The degradation time can be adjusted through the number
of lactic acid units incorporated into the monomer. However, prior
to polymerization, these monomers must be stored under anhydrous
conditions.
Another approach has been to synthesize crosslinkers containing
hydrolytically labile carbonate (Bruining et al, Biomaterials 21
(2000) 595-604), ester (Argade et al, Polymer Bulletin 31 (1993)
401-407), or phosphazene linkers (Grosse-Sommer et al, Journal of
Controlled Release 40 (1996) 261-267). These hydrogels are not
stable under any of the conditions described and begin to degrade
immediately following synthesis and exposure to an aqueous
environment. Yet another approach utilizes a reduction/oxidation
cleavable crosslinker, such as a disulfide bridge. However, the
reduction product from the disulfide bridge is two thiols, which
are easily reoxidized to the disulfide bridge, thereby restoring
the crosslink.
Still another approach would use a crosslinker that is stable under
either basic or acidic conditions, and starts to degrade at blood
pH, roughly 7.4. Ruckenstein et al (Ruckenstein et al,
Macromolecules, 32 (1999) 3979-3983; U.S. Pat. No. 6,323,360)
described one such crosslinker as the addition product between
ethylene glycol divinyl ether and methacrylic acid. The resulting
crosslinker, containing hemiacetal functional groups, is base
stable and degrades under acidic conditions. However, the
publication does not provide a means to control the degradation
time, nor are the described degradation conditions in organic
solvents meaningful for biological applications.
Another degradable crosslinker has been described by Ulbrich
(Ulbrich et al, Journal of Controlled Release, 24 (1993) 181-190;
Ulbrich et al, Journal of Controlled Release, 34 (1995) 155-165;
U.S. Pat. No. 5,130,479; U.S. Pat. No. 5,124,421). The crosslinker
is N,O-dimethacryloylhydroxylamine. The degradation of this
crosslinker is based on the base-catalyzed Lossen rearrangement of
substituted hydroxamic acids. The crosslinker appears to be stable
under acidic conditions, while degradation occurs at neutral to
basic pH. The only way disclosed by Ulbrich et al to control
degradation is through the crosslink density. Increasing the
crosslink density from 1.2% to 2.4% increases the degradation time
from 21 hours to 45 hours at pH 7.4 (U.S. Pat. No. 5,124,421).
Akala (Akala, Pharm Pharmacol Lett 8 (1998) 129-132) discovered
that the introduction of acrylic acid groups into a linear polymer
accelerated the degradation of the pendant N, O-diacylhydroxyamine
moieties, an effect not reported by Ulbrich et al.
SUMMARY OF THE INVENTION
In certain embodiments, the present invention relates to a compound
represented by 1: ##STR1##
wherein
X represents independently for each occurrence O or S;
L represents independently for each occurrence --O--NH--Q;
Q represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--;
R represents independently for each occurrence H or alkyl;
Z represents --NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--;
Ar represents independently for each occurrence aryl or
heteroaryl;
J represents independently for each occurrence O, S, NR,
cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2 O).sub.n, or (CH.sub.2
CH.sub.2 N(R).sub.n ;
n represents independently for each occurrence an integer in the
range 1-10; and
m represents independently for each occurrence an integer in the
range 0-10.
In certain embodiments, the present invention relates to a compound
represented by 1 and the attendant definitions, wherein X
represents O.
In certain embodiments, the present invention relates to a compound
represented by 1 and the attendant definitions, wherein L
represents --O--NH--Q.
In certain embodiments, the present invention relates to a compound
represented by 1 and the attendant definitions, wherein Q
represents acryloyl, or 2-methacryloyl.
In certain embodiments, the present invention relates to a compound
represented by 1 and the attendant definitions, wherein R
represents H.
In certain embodiments, the present invention relates to a compound
represented by 1 and the attendant definitions, wherein Z
represents --NH(CR.sub.2).sub.n NH--.
In certain embodiments, the present invention relates to a compound
represented by 1 and the attendant definitions, wherein X
represents O; and L represents --O--NH--Q.
In certain embodiments, the present invention relates to a compound
represented by 1 and the attendant definitions, wherein X
represents O; L represents --O--NH--Q; and Q represents acryloyl,
or 2-methacryloyl.
In certain embodiments, the present invention relates to a compound
represented by 1 and the attendant definitions, wherein X
represents O; L represents --O--NH--Q; Q represents acryloyl, or
2-methacryloyl; and R represents H.
In certain embodiments, the present invention relates to a compound
represented by 1 and the attendant definitions, wherein X
represents O; L represents --O--NH--Q; Q represents acryloyl, or
2-methacryloyl; R represents H; and Z represents
--NH(CR.sub.2).sub.n NH--.
In certain embodiments, the present invention relates to a compound
represented by 2: ##STR2##
wherein
X represents independently for each occurrence O or S;
M represents independently for each occurrence --O--NH--Q;
Q represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--;
R represents independently for each occurrence H or alkyl;
Z represents --NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--;
Ar represents independently for each occurrence aryl or
heteroaryl;
J represents independently for each occurrence O, S, NR,
cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2 O).sub.n, or (CH.sub.2
CH.sub.2 N(R)).sub.n ;
G represents (CR.sub.(4-t)), aryl, or heteroaryl;
n represents independently for each occurrence an integer in the
range 1-10;
m represents independently for each occurrence an integer in the
range 0-10; and
t represents 3 or 4.
In certain embodiments, the present invention relates to a compound
represented by 2 and the attendant definitions, wherein X
represents O.
In certain embodiments, the present invention relates to a compound
represented by 2 and the attendant definitions, wherein M
represents --O--NH--Q.
In certain embodiments, the present invention relates to a compound
represented by 2 and the attendant definitions, wherein Q
represents acryloyl, or 2-methacryloyl.
In certain embodiments, the present invention relates to a compound
represented by 2 and the attendant definitions, wherein R
represents H.
In certain embodiments, the present invention relates to a compound
represented by 2 and the attendant definitions, wherein X
represents O; and M represents --O--NH--Q.
In certain embodiments, the present invention relates to a compound
represented by 2 and the attendant definitions, wherein X
represents O; M represents --O--NH--Q; and Q represents acryloyl,
or 2-methacryloyl.
In certain embodiments, the present invention relates to a compound
represented by 2 and the attendant definitions, wherein X
represents O; M represents --O--NH--Q; Q represents acryloyl, or
2-methacryloyl; and R represents H.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1: ##STR3##
wherein
X represents independently for each occurrence O or S;
L represents independently for each occurrence --O--NH--Q;
Q represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--;
R represents independently for each occurrence H or alkyl;
Z represents --NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--;
Ar represents independently for each occurrence aryl or
heteroaryl;
J represents independently for each occurrence O, S, NR,
cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2 O).sub.n, or (CH.sub.2
CH.sub.2 N(R)).sub.n ;
n represents independently for each occurrence an integer in the
range 1-10; and
m represents independently for each occurrence an integer in the
range 0-10.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, wherein X represents O.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, wherein L represents --O--NH--Q.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, wherein Q represents acryloyl, or 2-methacryloyl.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, wherein R represents H.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, wherein Z represents --NH(CR.sub.2).sub.n NH--.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, wherein X represents O; and L represents
--O--NH--Q.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, wherein X represents O; L represents --O--NH--Q; and Q
represents acryloyl, or 2-methacryloyl.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, wherein X represents O; L represents --O--NH--Q; Q
represents acryloyl, or 2-methacryloyl; and R represents H.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, wherein X represents O; L represents --O--NH--Q; Q
represents acryloyl, or 2-methacryloyl; R represents H; and Z
represents --NH(CR.sub.2).sub.n NH--.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, further comprising a second monomer selected from the
group consisting of acrylic acids, acrylates, and acrylamides.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, further comprising a second monomer, wherein said
second monomer is acrylic acid, 2-hydroxyethyl acrylate,
oligo(ethylene glycol) 2-methacrylate, acrylamide,
N,N-dimethylacrylamide, or
N-(tris(hyrdoxymethyl)methyl)acrylamide.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2: ##STR4##
wherein
X represents independently for each occurrence O or S;
M represents independently for each occurrence --O--NH--Q;
Q represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--;
R represents independently for each occurrence H or alkyl;
Z represents --NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--;
Ar represents independently for each occurrence aryl or
heteroaryl;
J represents independently for each occurrence O, S, NR,
cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2 O).sub.n, or (CH.sub.2
CH.sub.2 N(R)).sub.n ;
G represents (CR.sub.(4-t)), aryl, or heteroaryl;
n represents independently for each occurrence an integer in the
range 1-10;
m represents independently for each occurrence an integer in the
range 0-10; and
t represents 3 or 4.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2 and the attendant
definitions, wherein X represents O.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2 and the attendant
definitions, wherein M represents --O--NH--Q.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2 and the attendant
definitions, wherein Q represents acryloyl, or 2-methacryloyl.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2 and the attendant
definitions, wherein R represents H.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2 and the attendant
definitions, wherein X represents O; and M represents
--O--NH--Q.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2 and the attendant
definitions, wherein X represents O; M represents --O--NH--Q; and Q
represents acryloyl, or 2-methacryloyl.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2 and the attendant
definitions, wherein X represents O; M represents --O--NH--Q; Q
represents acryloyl, or 2-methacryloyl; and R represents H.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2 and the attendant
definitions, further comprising a second monomer selected from the
group consisting of acrylic acids, acrylates, and acrylamides.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2 and the attendant
definitions, further comprising a second monomer, wherein said
second monomer is acrylic acid, 2-hydroxyethyl acrylate,
oligo(ethylene glycol) 2-methacrylate, acrylamide,
N,N-dimethylacrylamide, or
N-(tris(hyrdoxymethyl)methyl)acrylamide.
In certain embodiments, the present invention relates to a
crosslinked gel, comprising a hydrophobic polymer; and a
crosslinker selected from the group consisting of a compound
represented by 1 or 2 and one of the sets of attendant
definitions.
In certain embodiments, the present invention relates to a
crosslinked gel, comprising a hydrophobic polymer; and a
crosslinker selected from the group consisting of a compound
represented by 1 or 2 and one of the sets of attendant definitions,
wherein said hydrophobic polymer comprises an alkyl acrylate, alkyl
alkylacrylate, alkyl acrylamide, or alkyl alkylacrylamide.
In certain embodiments, the present invention relates to a
crosslinked gel, comprising a hydrophobic polymer; and a
crosslinker selected from the group consisting of a compound
represented by 1 or 2 and one of the sets of attendant definitions,
wherein said hydrophobic polymer comprises an alkyl
methacrylate.
In certain embodiments, the present invention relates to a
crosslinked gel, comprising a hydrophobic polymer; and a
crosslinker selected from the group consisting of a compound
represented by 1 or 2 and one of the sets of attendant definitions,
wherein said hydrophobic polymer comprises methyl methacrylate,
ethyl methacrylate, n-butyl methacrylate, or tert-butyl
methacrylate.
In certain embodiments, the present invention relates to a
crosslinked hydrogel, comprising a hydrophilic polymer; and a
crosslinker selected from the group consisting of a compound
represented by 1 or 2 and one of the sets of attendant
definitions.
In certain embodiments, the present invention relates to a
crosslinked hydrogel, comprising a hydrophilic polymer; and a
crosslinker selected from the group consisting of a compound
represented by 1 or 2 and one of the sets of attendant definitions,
wherein said hydrophilic polymer comprises an acrylic acid,
acrylate, or acrylamide.
In certain embodiments, the present invention relates to a
crosslinked hydrogel, comprising a hydrophilic polymer; and a
crosslinker selected from the group consisting of a compound
represented by 1 or 2 and one of the sets of attendant definitions,
wherein said hydrophilic polymer comprises acrylic acid,
2-hydroxyethyl acrylate, oligo(ethylene glycol) 2-methacrylate,
acrylamide, N,N-dimethylacrylamide, or
N-(tris(hydroxymethyl)methyl)acrylamide.
In certain embodiments, the present invention relates to a
crosslinked hydrogel, comprising a hydrophilic polymer; and a
crosslinker selected from the group consisting of a compound
represented by 1 or 2 and one of the sets of attendant definitions,
wherein said hydrophilic polymer consists of a first acrylamide and
a second acrylamide.
In certain embodiments, the present invention relates to a
crosslinked hydrogel, comprising a hydrophilic polymer; and a
crosslinker selected from the group consisting of a compound
represented by 1 or 2 and one of the sets of attendant definitions,
wherein said hydrophilic polymer consists of a first acrylamide and
a second acrylamide, wherein said first acrylamide is acrylamide or
N,N-dimethylacrylamide.
In certain embodiments, the present invention relates to a
crosslinked hydrogel, comprising a hydrophilic polymer; and a
crosslinker selected from the group consisting of a compound
represented by 1 or 2 and one of the sets of attendant definitions,
wherein said hydrophilic polymer consists of a first acrylamide and
a second acrylamide, wherein said second acrylamide is
N-(tris(hydroxymethyl)methyl)acrylamide.
In certain embodiments, the present invention relates to a
crosslinked hydrogel, comprising a hydrophilic polymer; and a
crosslinker selected from the group consisting of a compound
represented by 1 or 2 and one of the sets of attendant definitions,
wherein said hydrophilic polymer consists of a first acrylamide and
a second acrylamide, wherein said first acrylamide is acrylamide or
N,N-dimethylacrylamide; and said second acrylamide is
N-(tris(hydroxymethyl)methyl)acrylamide.
In certain embodiments, the present invention relates to a
crosslinked hydrogel, comprising a hydrophilic polymer; and a
crosslinker selected from the group consisting of a compound
represented by 1 or 2 and one of the sets of attendant definitions,
wherein said hydrophilic polymer consists of an acrylamide and an
acrylate.
In certain embodiments, the present invention relates to a
crosslinked hydrogel, comprising a hydrophilic polymer; and a
crosslinker selected from the group consisting of a compound
represented by 1 or 2 and one of the sets of attendant definitions,
wherein said hydrophilic polymer consists of an acrylamide and an
acrylate, wherein said acrylamide is acrylamide or
N,N-dimethylacrylamide.
In certain embodiments, the present invention relates to a
crosslinked hydrogel, comprising a hydrophilic polymer; and a
crosslinker selected from the group consisting of a compound
represented by 1 or 2 and one of the sets of attendant definitions,
wherein said hydrophilic polymer consists of an acrylamide and an
acrylate, wherein said acrylate is acrylic acid, 2-hydroxyethyl
acrylate, or oligo(ethylene glycol) 2-methacrylate.
In certain embodiments, the present invention relates to a
crosslinked hydrogel, comprising a hydrophilic polymer; and a
crosslinker selected from the group consisting of a compound
represented by 1 or 2 and one of the sets of attendant definitions,
wherein said hydrophilic polymer consists of an acrylamide and an
acrylate, wherein said acrylamide is acrylamide or
N,N-dimethylacrylamide; and said acrylate is acrylic acid,
2-hydroxyethyl acrylate, or oligo(ethylene glycol)
2-methacrylate.
In certain embodiments, the present invention relates to a
crosslinked hydrogel, comprising a hydrophilic polymer; and a
crosslinker selected from the group consisting of a compound
represented by 1 or 2 and one of the sets of attendant definitions,
wherein said hydrophilic polymer consists of a first acrylate and a
second acrylate.
In certain embodiments, the present invention relates to a
crosslinked hydrogel, comprising a hydrophilic polymer; and a
crosslinker selected from the group consisting of a compound
represented by 1 or 2 and one of the sets of attendant definitions,
wherein said hydrophilic polymer consists of a first acrylate and a
second acrylate, wherein said first acrylate is acrylic acid,
2-hydroxyethyl acrylate, or oligo(ethylene glycol)
2-methacrylate.
In certain embodiments, the present invention relates to a
crosslinked hydrogel, comprising a hydrophilic polymer; and a
crosslinker selected from the group consisting of a compound
represented by 1 or 2 and one of the sets of attendant definitions,
wherein said hydrophilic polymer consists of a first acrylate and a
second acrylate, wherein said first acrylate is acrylic acid,
2-hydroxyethyl acrylate, or oligo(ethylene glycol) 2-methacrylate;
and said second acrylate is acrylic acid, 2-hydroxyethyl acrylate,
or oligo(ethylene glycol) 2-methacrylate.
In certain embodiments, the present invention relates to a method
of preparing a compound represented by 1: ##STR5##
wherein
X represents independently for each occurrence O or S;
L represents independently for each occurrence --O--NH--Q;
Q represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--;
R represents independently for each occurrence H or alkyl;
Z represents --NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--;
Ar represents independently for each occurrence aryl or
heteroaryl;
J represents independently for each occurrence O, S, NR,
cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2 O).sub.n, or (CH.sub.2
CH.sub.2 N(R)).sub.n ;
n represents independently for each occurrence an integer in the
range 1-10; and
m represents independently for each occurrence an integer in the
range 0-10;
comprising:
(a) reacting a hydroxylamine with an acrylate, thereby forming an
acrylic hydroxamic acid; and
(b) reacting said acrylic hydroxamic acid with a diisocyanate.
In certain embodiments, the present invention relates to a method
of preparing a compound represented by 2: ##STR6##
wherein
X represents independently for each occurrence O or S;
M represents independently for each occurrence --O--NH--Q;
Q represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--;
R represents independently for each occurrence H or alkyl;
Z represents --NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--;
Ar represents independently for each occurrence aryl or
heteroaryl;
J represents independently for each occurrence O, S, NR,
cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2 O).sub.n, or (CH.sub.2
CH.sub.2 N(R)).sub.n ;
G represents (CR.sub.(4-t)), aryl, or heteroaryl;
n represents independently for each occurrence an integer in the
range 1-10;
m represents independently for each occurrence an integer in the
range 0-10; and
t represents 3 or 4;
comprising:
(a) reacting a hydroxylamine with an acrylate, thereby forming a
hydroxamic acid; and
(b) reacting said hydroxamic acid with a triisocyanate or
tetraisocyanate.
In certain embodiments, the present invention relates to a method
of preparing a polymer comprising a monomer represented by 1:
##STR7##
wherein
X represents independently for each occurrence O or S;
L represents independently for each occurrence --O--NH--Q;
Q represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--;
R represents independently for each occurrence H or alkyl;
Z represents --NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--;
Ar represents independently for each occurrence aryl or
heteroaryl;
J represents independently for each occurrence O, S, NR,
cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2 O).sub.n, or (CH.sub.2
CH.sub.2 N(R)).sub.n ;
n represents independently for each occurrence an integer in the
range 1-10; and
m represents independently for each occurrence an integer in the
range 0-10;
comprising:
a) reacting a monomer represented by 1 with a second monomer in the
presence of an initiator.
In certain embodiments, the present invention relates to a method
of preparing a polymer comprising a monomer represented by 2:
##STR8##
wherein
X represents independently for each occurrence O or S;
M represents independently for each occurrence --O--NH--Q;
Q represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--;
R represents independently for each occurrence H or alkyl;
Z represents --NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--;
Ar represents independently for each occurrence aryl or
heteroaryl;
J represents independently for each occurrence O, S, NR,
cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2 O).sub.n, or (CH.sub.2
CH.sub.2 N(R)).sub.n ;
G represents (CR.sub.(4-t)), aryl, or heteroaryl;
n represents independently for each occurrence an integer in the
range 1-10;
m represents independently for each occurrence an integer in the
range 0-10; and
t represents 3 or 4;
comprising:
a) reacting a monomer represented by 2 with a second monomer in the
presence of an initiator.
In certain embodiments, the present invention relates to a method
of preparing a crosslinked gel, comprising a hydrophobic polymer,
and a crosslinker represented by 1: ##STR9##
wherein
X represents independently for each occurrence O or S;
L represents independently for each occurrence --O--NH--Q;
Q represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--;
R represents independently for each occurrence H or alkyl;
Z represents --NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m --;
Ar represents independently for each occurrence aryl or
heteroaryl;
J represents independently for each occurrence O, S, NR,
cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2 O).sub.n, or (CH.sub.2
CH.sub.2 N(R)).sub.n ;
n represents independently for each occurrence an integer in the
range 1-10; and
m represents independently for each occurrence an integer in the
range 0-10;
comprising:
a) reacting a monomer represented by 1 with a hydrophobic monomer
in the presence of an initiator.
In certain embodiments, the present invention relates to a method
of preparing a crosslinked gel comprising a hydrophobic polymer and
a crosslinker represented by 2: ##STR10##
wherein
X represents independently for each occurrence O or S;
M represents independently for each occurrence --O--NH--Q;
Q represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n --,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--;
R represents independently for each occurrence H or alkyl;
Z represents --NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--;
Ar represents independently for each occurrence aryl or
heteroaryl;
J represents independently for each occurrence O, S, NR,
cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2 O).sub.n, or (CH.sub.2
CH.sub.2 N(R)).sub.n ;
G represents (CR.sub.(4-t)), aryl, or heteroaryl;
n represents independently for each occurrence an integer in the
range 1-10;
m represents independently for each occurrence an integer in the
range 0-10; and
t represents 3 or 4;
comprising:
a) reacting a monomer represented by 2 with a hydrophobic monomer
in the presence of an initiator.
In certain embodiments, the present invention relates to a method
of preparing a crosslinked hydrogel, comprising a hydrophilic
polymer and a crosslinker represented by 1: ##STR11##
wherein
X represents independently for each occurrence O or S;
L represents independently for each occurrence --O--NH--Q;
Q represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--;
R represents independently for each occurrence H or alkyl;
Z represents --NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--;
Ar represents independently for each occurrence aryl or
heteroaryl;
J represents independently for each occurrence O, S, NR,
cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2 O).sub.n, or (CH.sub.2
CH.sub.2 N(R)).sub.n ;
n represents independently for each occurrence an integer in the
range 1-10; and
m represents independently for each occurrence an integer in the
range 0-10;
comprising:
a) reacting a monomer represented by 1 with a hydrophilic monomer
in the presence of an initiator.
In certain embodiments, the present invention relates to a method
of preparing a crosslinked hydrogel, comprising a hydrophilic
polymer and a crosslinker represented by 2: ##STR12##
wherein
X represents independently for each occurrence O or S;
M represents independently for each occurrence --O--NH--Q;
Q represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--;
R represents independently for each occurrence H or alkyl;
Z represents --NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--;
Ar represents independently for each occurrence aryl or
heteroaryl;
J represents independently for each occurrence O, S, NR,
cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2 O).sub.n, or (CH.sub.2
CH.sub.2 N(R)).sub.n ;
G represents (CR.sub.(4-t)), aryl, or heteroaryl;
n represents independently for each occurrence an integer in the
range 1-10;
m represents independently for each occurrence an integer in the
range 0-10; and
t represents 3 or 4;
comprising:
a) reacting a monomer represented by 1 with a hydrophilic monomer
in the presence of an initiator.
DETAILED DESCRIPTION OF THE INVENTION
One aspect of the present invention relates to base-labile,
carbamate-containing crosslinkers. A second aspect of the present
invention relates to degradable crosslinked polymers and hydrogels
comprising a base-labile, carbamate-containing crosslinker. The
present invention also relates to methods of preparing base-labile,
carbamate-containing crosslinkers. Another aspect of the present
invention relates to methods of preparing cross-linked polymers and
hydrogels comprising a base-labile, carbamate-containing
crosslinker.
Definitions
For convenience, certain terms employed in the specification,
examples, and appended claims are collected here.
The articles "a" and "an" are used herein to refer to one or to
more than one (i.e., to at least one) of the grammatical object of
the article. By way of example, "an element" means one element or
more than one element.
The term "crosslinking agent", as used herein, refers to any
chemical agent that joins distinct chains of a polymer through
covalent bonds.
The term "initiator", as used herein, refers to any compound which
initiates polymerization, or produces a reactive species which
initiates polymerization.
The term "polymer", as used herein, refers to a natural or
synthetic compound of unusually high molecular weight consisting of
a repeating monomeric unit.
The term "polymerization", as used herein, refers to the bonding of
two or more monomers to form a polymer.
The term "monomer", as used herein, refers to a molecule that can
combine with another to form a polymer; it is the repeating unit of
a polymer.
The term "biocompatible", as used herein, refers to having the
property of being biologically compatible by not producing a toxic,
injurious, or immunological response in living tissue.
The term "degradable", as used herein, refers to having the
property of breaking down or degrading under certain conditions,
e.g., at neutral or basic pH.
The term "hydrogel", as used herein refers to a type of gel in
which the disperse phase has combined with water to produce a
semisolid material.
The term "heteroatom" as used herein means an atom of any element
other than carbon or hydrogen. Preferred heteroatoms are boron,
nitrogen, oxygen, phosphorus, sulfur and selenium.
The term "alkyl" refers to the radical of saturated aliphatic
groups, including straight-chain alkyl groups, branched-chain alkyl
groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl
groups, and cycloalkyl substituted alkyl groups. In preferred
embodiments, a straight chain or branched chain alkyl has 30 or
fewer carbon atoms in its backbone (e.g., C.sub.1 -C.sub.30 for
straight chain, C.sub.3 -C.sub.30 for branched chain), and more
preferably 20 or fewer. Likewise, preferred cycloalkyls have from
3-10 carbon atoms in their ring structure, and more preferably have
5, 6 or 7 carbons in the ring structure.
Unless the number of carbons is otherwise specified, "lower alkyl"
as used herein means an alkyl group, as defined above, but having
from one to ten carbons, more preferably from one to six carbon
atoms in its backbone structure. Likewise, "lower alkenyl" and
"lower alkynyl" have similar chain lengths. Preferred alkyl groups
are lower alkyls. In preferred embodiments, a substituent
designated herein as alkyl is a lower alkyl.
The term "aralkyl", as used herein, refers to an alkyl group
substituted with an aryl group (e.g., an aromatic or heteroaromatic
group).
The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic
groups analogous in length and possible substitution to the alkyls
described above, but that contain at least one double or triple
bond respectively.
The term "aryl" as used herein includes 5-, 6- and 7-membered
single-ring aromatic groups that may include from zero to four
heteroatoms, for example, benzene, naphthalene, anthracene, pyrene,
pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole,
pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the
like. Those aryl groups having heteroatoms in the ring structure
may also be referred to as "aryl heterocycles" or
"heteroaromatics." The aromatic ring can be substituted at one or
more ring positions with such substituents as described above, for
example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,
cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino,
amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether,
alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester,
heterocyclyl, aromatic or heteroaromatic moieties, --CF.sub.3,
--CN, or the like. The term "aryl" also includes polycyclic ring
systems having two or more cyclic rings in which two or more
carbons are common to two adjoining rings (the rings are "fused
rings") wherein at least one of the rings is aromatic, e.g., the
other cyclic rings can be cycloalkyls, cycloalkenyls,
cycloalkynyls, aryls and/or heterocyclyls.
The terms ortho, meta and para apply to 1,2-, 1,3- and
1,4-disubstituted benzenes, respectively. For example, the names
1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
The terms "heterocyclyl" or "heterocyclic group" refer to 3- to
10-membered ring structures, more preferably 3- to 7-membered
rings, whose ring structures include one to four heteroatoms.
Heterocycles can also be polycycles. Heterocyclyl groups include,
for example, azetidine, azepine, thiophene, thianthrene, furan,
pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole,
imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine,
pyrimidine, pyridazine, indolizine, isoindole, indole, indazole,
purine, quinolizine, isoquinoline, quinoline, phthalazine,
naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine,
carbazole, carboline, phenanthridine, acridine, pyrimidine,
phenanthroline, phenazine, phenarsazine, phenothiazine, furazan,
phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine,
piperazine, morpholine, lactones, lactams such as azetidinones and
pyrrolidinones, sultams, sultones, and the like. The heterocyclic
ring can be substituted at one or more positions with such
substituents as described above, as for example, halogen, alkyl,
aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro,
sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl,
carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde,
ester, a heterocyclyl, an aromatic or heteroaromatic moiety,
--CF.sub.3, --CN, or the like.
The terms "polycyclyl" or "polycyclic group" refer to two or more
rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls
and/or heterocyclyls) in which two or more carbons are common to
two adjoining rings, e.g., the rings are "fused rings". Rings that
are joined through non-adjacent atoms are termed "bridged" rings.
Each of the rings of the polycycle can be substituted with such
substituents as described above, as for example, halogen, alkyl,
aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro,
sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl,
carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde,
ester, a heterocyclyl, an aromatic or heteroaromatic moiety,
--CF.sub.3, --CN, or the like.
The term "carbocycle", as used herein, refers to an aromatic or
non-aromatic ring in which each atom of the ring is carbon.
As used herein, the term "nitro" means --NO.sub.2 ; the term
"halogen" designates --F, --Cl, --Br or --I; the term "sulfhydryl"
means --SH; the term "hydroxyl" means --OH; and the term "sulfonyl"
means --SO.sub.2 --.
The terms "amine" and "amino" are art-recognized and refer to both
unsubstituted and substituted amines, e.g., a moiety that can be
represented by the general formula: ##STR13##
wherein R.sub.9, R.sub.10 and R'.sub.10 each independently
represent a group permitted by the rules of valence.
The term "acylamino" is art-recognized and refers to a moiety that
can be represented by the general formula: ##STR14##
wherein R.sub.9 is as defined above, and R'.sub.11 represents a
hydrogen, an alkyl, an alkenyl or --(CH.sub.2).sub.m --R.sub.8,
where m and R.sub.8 are as defined above.
The term "amido" is art recognized as an amino-substituted carbonyl
and includes a moiety that can be represented by the general
formula: ##STR15##
wherein R.sub.9, R.sub.10 are as defined above. Preferred
embodiments of the amide will not include imides which may be
unstable.
The term "alkylthio" refers to an alkyl group, as defined above,
having a sulfur radical attached thereto. In preferred embodiments,
the "alkylthio" moiety is represented by one of --S-alkyl,
--S-alkenyl, --S-alkynyl, and --S--(CH.sub.2).sub.m --R.sub.8,
wherein m and R.sub.8 are defined above. Representative alkylthio
groups include methylthio, ethyl thio, and the like.
The term "carbonyl" is art recognized and includes such moieties as
can be represented by the general formula: ##STR16##
wherein X is a bond or represents an oxygen or a sulfur, and
R.sub.11 represents a hydrogen, an alkyl, an alkenyl,
--(CH.sub.2).sub.m --R.sub.8 or a pharmaceutically acceptable salt,
R'.sub.11 represents a hydrogen, an alkyl, an alkenyl or
--(CH.sub.2).sub.m --R.sub.8, where m and R.sub.8 are as defined
above. Where X is an oxygen and R.sub.11 or R'.sup.11 is not
hydrogen, the formula represents an "ester". Where X is an oxygen,
and R.sub.11 is as defined above, the moiety is referred to herein
as a carboxyl group, and particularly when R.sub.11 is a hydrogen,
the formula represents a "carboxylic acid". Where X is an oxygen,
and R'.sub.11 is hydrogen, the formula represents a "formate". In
general, where the oxygen atom of the above formula is replaced by
sulfur, the formula represents a "thiolcarbonyl" group. Where X is
a sulfur and R.sub.11 or R'.sub.11 is not hydrogen, the formula
represents a "thiolester." Where X is a sulfur and R.sub.11 is
hydrogen, the formula represents a "thiolcarboxylic acid." Where X
is a sulfur and R.sub.11 ' is hydrogen, the formula represents a
"thiolformate." On the other hand, where X is a bond, and R.sub.11
is not hydrogen, the above formula represents a "ketone" group.
Where X is a bond, and R.sub.11 is hydrogen, the above formula
represents an "aldehyde" group.
The terms "alkoxyl" or "alkoxy" as used herein refers to an alkyl
group, as defined above, having an oxygen radical attached thereto.
Representative alkoxyl groups include methoxy, ethoxy, propyloxy,
tert-butoxy and the like. An "ether" is two hydrocarbons covalently
linked by an oxygen. Accordingly, the substituent of an alkyl that
renders that alkyl an ether is or resembles an alkoxyl, such as can
be represented by one of --O-alkyl, --O-alkenyl, --O-alkynyl,
--O--(CH.sub.2).sub.m --R.sub.8, where m and R.sub.8 are described
above.
The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl,
ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,
p-toluenesulfonyl and methanesulfonyl, respectively. A more
comprehensive list of the abbreviations utilized by organic
chemists of ordinary skill in the art appears in the first issue of
each volume of the Journal of Organic Chemistry; this list is
typically presented in a table entitled Standard List of
Abbreviations. The abbreviations contained in said list, and all
abbreviations utilized by organic chemists of ordinary skill in the
art are hereby incorporated by reference.
Analogous substitutions can be made to alkenyl and alkynyl groups
to produce, for example, aminoalkenyls, aminoalkynyls,
amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls,
thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or
alkynyls.
As used herein, the definition of each expression, e.g. alkyl, m,
n, etc., when it occurs more than once in any structure, is
intended to be independent of its definition elsewhere in the same
structure.
It will be understood that "substitution" or "substituted with"
includes the implicit proviso that such substitution is in
accordance with permitted valence of the substituted atom and the
substituent, and that the substitution results in a stable
compound, e.g., which does not spontaneously undergo transformation
such as by rearrangement, cyclization, elimination, etc.
As used herein, the term "substituted" is contemplated to include
all permissible substituents of organic compounds. In a broad
aspect, the permissible substituents include acyclic and cyclic,
branched and unbranched, carbocyclic and heterocyclic, aromatic and
nonaromatic substituents of organic compounds. Illustrative
substituents include, for example, those described herein above.
The permissible substituents can be one or more and the same or
different for appropriate organic compounds. For purposes of this
invention, the heteroatoms such as nitrogen may have hydrogen
substituents and/or any permissible substituents of organic
compounds described herein which satisfy the valences of the
heteroatoms. This invention is not intended to be limited in any
manner by the permissible substituents of organic compounds.
The phrase "protecting group" as used herein means temporary
substituents which protect a potentially reactive functional group
from undesired chemical transformations. Examples of such
protecting groups include esters of carboxylic acids, silyl ethers
of alcohols, and acetals and ketals of aldehydes and ketones,
respectively. The field of protecting group chemistry has been
reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2.sup.nd ed.; Wiley: New York, 1991).
Certain compounds of the present invention may exist in particular
geometric or stereoisomeric forms. The present invention
contemplates all such compounds, including cis- and trans-isomers,
R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the
racemic mixtures thereof, and other mixtures thereof, as falling
within the scope of the invention. Additional asymmetric carbon
atoms may be present in a substituent such as an alkyl group. All
such isomers, as well as mixtures thereof, are intended to be
included in this invention.
If, for instance, a particular enantiomer of a compound of the
present invention is desired, it may be prepared by asymmetric
synthesis, it may be isolated using chiral chromatography methods,
or by derivation with a chiral auxiliary, where the resulting
diastereomeric mixture is separated and the auxiliary group cleaved
to provide the pure desired enantiomers. Alternatively, where the
molecule contains a basic functional group, such as amino, or an
acidic functional group, such as carboxyl, diastereomeric salts are
formed with an appropriate optically-active acid or base, followed
by resolution of the diastereomers thus formed by fractional
crystallization or chromatographic means well known in the art, and
subsequent recovery of the pure enantiomers.
Contemplated equivalents of the compounds described above include
compounds which otherwise correspond thereto, and which have the
same general properties thereof (e.g., functioning as analgesics),
wherein one or more simple variations of substituents are made
which do not adversely affect the efficacy of the compound in
binding to opioid receptors. In general, the compounds of the
present invention may be prepared by the methods illustrated in the
general reaction schemes as, for example, described below, or by
modifications thereof, using readily available starting materials,
reagents and conventional synthesis procedures. In these reactions,
it is also possible to make use of variants which are in themselves
known, but are not mentioned here.
For purposes of this invention, the chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87,
inside cover.
Compounds of the Invention
In certain embodiments, the present invention relates to a compound
represented by 1: ##STR17##
wherein
X represents independently for each occurrence O or S;
L represents independently for each occurrence --O--NH--Q;
Q represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--;
R represents independently for each occurrence H or alkyl;
Z represents --NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--;
Ar represents independently for each occurrence aryl or
heteroaryl;
J represents independently for each occurrence O, S, NR,
cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2 O).sub.n, or (CH.sub.2
CH.sub.2 N(R)).sub.n ;
n represents independently for each occurrence an integer in the
range 1-10; and
m represents independently for each occurrence an integer in the
range 0-10.
In certain embodiments, the present invention relates to a compound
represented by 1 and the attendant definitions, wherein X
represents O.
In certain embodiments, the present invention relates to a compound
represented by 1 and the attendant definitions, wherein L
represents --O--NH--Q.
In certain embodiments, the present invention relates to a compound
represented by 1 and the attendant definitions, wherein Q
represents acryloyl, or 2-methacryloyl.
In certain embodiments, the present invention relates to a compound
represented by 1 and the attendant definitions, wherein R
represents H.
In certain embodiments, the present invention relates to a compound
represented by 1 and the attendant definitions, wherein Z
represents --NH(CR.sub.2).sub.n NH--.
In certain embodiments, the present invention relates to a compound
represented by 1 and the attendant definitions, wherein X
represents O; and L represents --O--NH--Q.
In certain embodiments, the present invention relates to a compound
represented by 1 and the attendant definitions, wherein X
represents O; L represents --O--NH--Q; and Q represents acryloyl,
or 2-methacryloyl.
In certain embodiments, the present invention relates to a compound
represented by 1 and the attendant definitions, wherein X
represents O; L represents --O--NH--Q; Q represents acryloyl, or
2-methacryloyl; and R represents H.
In certain embodiments, the present invention relates to a compound
represented by 1 and the attendant definitions, wherein X
represents O; L represents --O--NH--Q; Q represents acryloyl, or
2-methacryloyl; R represents H; and Z represents
--NH(CR.sub.2).sub.n NH--.
In certain embodiments, the present invention relates to a method
of preparing a compound represented by 1 and the attendant
definitions, comprising reacting a hydroxylamine with an acrylate,
thereby forming an acrylic hydroxamic acid; and reacting said
acrylic hydroxamic acid with a diisocyanate.
In certain embodiments, the present invention relates to a compound
represented by 2: ##STR18##
wherein
X represents independently for each occurrence O or S;
M represents independently for each occurrence --O--NH--Q;
Q represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--;
R represents independently for each occurrence H or alkyl;
Z represents --NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--;
Ar represents independently for each occurrence aryl or
heteroaryl;
J represents independently for each occurrence O, S, NR,
cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2 O).sub.n, or (CH.sub.2
CH.sub.2 N(R)).sub.n ;
G represents (CR.sub.(4-t)), aryl, or heteroaryl;
n represents independently for each occurrence an integer in the
range 1-10;
m represents independently for each occurrence an integer in the
range 0-10; and
t represents 3 or 4.
In certain embodiments, the present invention relates to a compound
represented by 2 and the attendant definitions, wherein X
represents O.
In certain embodiments, the present invention relates to a compound
represented by 2 and the attendant definitions, wherein M
represents --O--NH--Q.
In certain embodiments, the present invention relates to a compound
represented by 2 and the attendant definitions, wherein Q
represents acryloyl, or 2-methacryloyl.
In certain embodiments, the present invention relates to a compound
represented by 2 and the attendant definitions, wherein R
represents H.
In certain embodiments, the present invention relates to a compound
represented by 2 and the attendant definitions, wherein X
represents O; and M represents --O--NH--Q.
In certain embodiments, the present invention relates to a compound
represented by 2 and the attendant definitions, wherein X
represents O; M represents --O--NH--Q; and Q represents acryloyl,
or 2-methacryloyl.
In certain embodiments, the present invention relates to a compound
represented by 2 and the attendant definitions, wherein X
represents O; M represents --O--NH--Q; Q represents acryloyl, or
2-methacryloyl; and R represents H.
In certain embodiments, the present invention relates to a method
of preparing a compound represented by 2 and the attendant
definitions, comprising reacting a hydroxylamine with an acrylate,
thereby forming a hydroxamic acid; and reacting said hydroxamic
acid with a triisocyanate or tetraisocyanate.
Polymers of the Invention
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1: ##STR19##
wherein
X represents independently for each occurrence O or S;
L represents independently for each occurrence --O--NH--Q;
Q represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--;
R represents independently for each occurrence H or alkyl;
Z represents --NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--;
Ar represents independently for each occurrence aryl or
heteroaryl;
J represents independently for each occurrence O, S, NR,
cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2 O).sub.n, or (CH.sub.2
CH.sub.2 N(R)).sub.n ;
n represents independently for each occurrence an integer in the
range 1-10; and
m represents independently for each occurrence an integer in the
range 0-10.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, wherein X represents O.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, wherein L represents --O--NH--Q.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, wherein Q represents acryloyl, or 2-methacryloyl.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, wherein R represents H.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, wherein Z represents --NH(CR.sub.2).sub.n NH--.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, wherein X represents O; and L represents
--O--NH--Q.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, wherein X represents O; L represents --O--NH--Q; and Q
represents acryloyl, or 2-methacryloyl.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, wherein X represents O; L represents --O--NH--Q; Q
represents acryloyl, or 2-methacryloyl; and R represents H.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, wherein X represents O; L represents --O--NH--Q; Q
represents acryloyl, or 2-methacryloyl; R represents H; and Z
represents --NH(CR.sub.2).sub.n NH--.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, further comprising a second monomer selected from the
group consisting of acrylic acids, acrylates, and acrylamides.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 1 and the attendant
definitions, further comprising a second monomer, wherein said
second monomer is acrylic acid, 2-hydroxyethyl acrylate,
oligo(ethylene glycol) 2-methacrylate, acrylamide,
N,N-dimethylacrylamide, or
N-(tris(hyrdoxymethyl)methyl)acrylamide.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2: ##STR20##
wherein
X represents independently for each occurrence O or S;
M represents independently for each occurrence --O--NH--Q;
Q represents independently for each occurrence acryloyl,
2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl,
3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl,
acryloylO(CR.sub.2).sub.n C(O)--, 2-alkylacryloylO(CR.sub.2).sub.n
C(O)--, 3-alkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
3,3-dialkylacryloylO(CR.sub.2).sub.n C(O)--,
2,3,3-trialkylacryloylO(CR.sub.2).sub.n C(O)--, (diene)C(O)--,
(vinyl)(CR.sub.2).sub.n C(O)--, or (vinyl)ArC(O)--;
R represents independently for each occurrence H or alkyl;
Z represents --NH(CR.sub.2).sub.n NH--, or --NH(CR.sub.2).sub.n
J(CR.sub.2).sub.m NH--;
Ar represents independently for each occurrence aryl or
heteroaryl;
J represents independently for each occurrence O, S, NR,
cycloalkyl, heterocyclyl, (CH.sub.2 CH.sub.2 O)n, or (CH.sub.2
CH.sub.2 N(R)).sub.n ;
G represents (CR.sub.(4-t)), aryl, or heteroaryl;
n represents independently for each occurrence an integer in the
range 1-10;
m represents independently for each occurrence an integer in the
range 0-10; and
t represents 3 or 4.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2 and the attendant
definitions, wherein X represents O. In certain embodiments, the
present invention relates to a polymer, comprising a monomer
represented by 2 and the attendant definitions, wherein M
represents --O--NH--Q.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2 and the attendant
definitions, wherein Q represents acryloyl, or 2-methacryloyl.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2 and the attendant
definitions, wherein R represents H.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2 and the attendant
definitions, wherein X represents O; and M represents
--O--NH--Q.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2 and the attendant
definitions, wherein X represents O; M represents --O--NH--Q; and Q
represents acryloyl, or 2-methacryloyl.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2 and the attendant
definitions, wherein X represents O; M represents --O--NH--Q; Q
represents acryloyl, or 2-methacryloyl; and R represents H.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2 and the attendant
definitions, further comprising a second monomer selected from the
group consisting of acrylic acids, acrylates, and acrylamides.
In certain embodiments, the present invention relates to a polymer,
comprising a monomer represented by 2 and the attendant
definitions, further comprising a second monomer, wherein said
second monomer is acrylic acid, 2-hydroxyethyl acrylate,
oligo(ethylene glycol) 2-methacrylate, acrylamide,
N,N-dimethylacrylamide, or
N-(tris(hyrdoxymethyl)methyl)acrylamide.
Gels and Hydrogels of the Invention
Hydrogels are a well recognized class of polymeric materials. These
materials are characterized by their water-insolubility,
hydrophilicity, high-water absorbability and swellable properties.
The molecular components or units or segments of the hydrogel are
characterized by a significant portion of hydrophilic components,
units or segments, such as segments having ionic species or
dissociable species such as acids (e.g., carboxylic acids,
phosphonic acids, sulfonic acids, sulfinic acids, phosphinic acids,
etc.), bases (e.g., amine groups, proton accepting groups), or
other groups that develop ionic properties when immersed in water
(e.g., sulfonamides). Acryloyl groups (and to a lesser degree
methacryloyl groups) and the class of acrylic polymers, polymer
chains containing or terminated with oxyalkylene units (such as
polyoxyethylene chains or polyoxyethylene/polyoxypropylene
copolymer chains) are also well recognized as hydrophilic segments
that may be present within hydrophilic polymers
Certain preferred water insoluble polymeric compositions useful in
the present invention are listed below, although the entire class
of hydrogel materials known in the art may be used to various
degrees. The polymers set forth below and containing acid groups
can be, as an option, partially or completely neutralized with
alkali metal bases either as the monomer or the polymer or both.
While the list below contains many of the preferred polymers which
may be used in accordance with the present invention, the present
invention is not limited to just these polymers and generally
polymers traditionally understood as hydrogels by those skilled in
the art can also be used: a) polyacrylic acid, polymethacrylic
acid, polymaleic acid, copolymers thereof, and alkali metal and
ammonium salts thereof; b) graft copolymers of starch and acrylic
acid, starch and saponified acrylonitrile, starch and saponified
ethyl acrylate, and acrylate-vinyl acetate copolymers saponified;
c) polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl alkylether,
polyethylene oxide, polyacrylamide, and copolymers thereof; d)
copolymers of maleic anhydride and alkyl vinylethers; and e)
saponified starch graft copolymers of acrylonitrile, acrylate
esters, vinyl acetate, and starch graft copolymers of acrylic acid,
methylacrylic acid, and maleic acid.
The above exemplary polymers are cross-linked either during the
polymerization or after the core is encapsulated. This
cross-linking is achieved using the cross-linking agents of the
present invention by methods known to those skilled in the art.
This cross-linking can be initiated in the presence of radiation or
a chemical free radical initiator.
One of the useful properties of hydrogels is their ability to
absorb water and swell without dissolution of the matrix. As the
hydrogel swells, the pore size of the hydrogel increases which
enhances uptake of aqueous solutions and the diffusion of compounds
out of the hydrogel. These properties have allowed use of hydrogels
as controlled drug release systems and as absorbent materials.
However, the rate of swelling of dried hydrogels upon exposure to
an aqueous solution is limited by diffusion of water into the
glassy polymer matrix. Conventional dried hydrogels have relatively
small pore sizes resulting in slow swelling and release or
absorption of liquids. The size of the pores in the hydrogel can be
a factor used in the selection of hydrogels with the appropriate
properties for the specific removable caps in the practice of the
present invention. The larger the pore size, the generally higher
rate of initial swelling a hydrogel undergoes.
Among the many hydrogel polymers which are useful as matrix
polymers include poly(hydroxyalkyl methacrylate)s of which
poly-(2-hydroxyethyl methacrylate), poly(glyceryl methacrylate) and
poly(hydroxypropyl methacrylate) are well-known and identified in
the literature as (P-HEMA), (P-GMA) and (P-(HPMA), respectively.
Other hydrogel polymers include poly(acrylamide),
poly(methacrylamide), poly(N-vinyl-2-pyrrolidine), and poly(vinyl
alcohol), hydroxypropyl guar, high molecular weight polypropylene
glycol or polyethylene glycol, and the like. It is known to produce
sparingly cross-linked, water-insoluble but hydrophilic polymers
which can be used as carriers for biologically active, at least
slightly water-soluble substances by copolymerization of a major
amount of hydrophilic mono-olefinic monomers and a minor amount
ranging between 0.01 and 15% of said mono-olefinic monomers, of a
low molecular weight cross-linker. As mono-olefinic monomers,
particularly monoesters of acrylic or methacrylic acid with
polyfunctional alcohols, such as ethyleneglycol monomethacrylate,
and as cross-linking agents particularly diesters of said acids
with said alcohols, such as ethyleneglycol bis-methacrylate are
used and the copolymerization is carried out in the presence of
water, see U.S. Pat. No. 3,220,960 or a water-free system, see U.S.
Pat. No. 3,520,949. Low molecular as well as macromolecular,
water-soluble substances, such as polyethyleneoxide
mono-methacrylate together with a minor amount of the corresponding
bis-methacrylate have been used (see U.S. Pat. No. 3,220,960) as
monomers and cross-linking agents. The water-insoluble, but
hydrophilic copolymers and the process for their production have
been modified in several directions and adapted to specific
purposes, e.g. the production of soft contact lenses, U.S. Pat. No.
3,220,960 and Reissue No. 27,401, and the copolymerization in the
presence of linear polyamide resin in order to improve or modify
the mechanical properties of shaped bodies formed from the obtained
polymers, U.S. Pat. No. 3,520,949.
Non-limiting examples of the unsaturated monomers used as a
starting material include those polymerizable monomers known to be
soluble in water. Examples of these unsaturated monomer are:
monomers containing an acid group, such as acrylic acid,
beta-acryloyloxypropionic acid, methacrylic acid, crotonic acid,
maleic acid, maleic anhydride, fumaric acid, itaconic acid,
cinnamic acid, sorbic acid, 2-(meth)acryloylethane sulfonic acid,
2-(meth)acryloylpropane sulfonic acid,
2-(meth)acrylamido-2-methylpropane sulfonic acid, vinyl sulfonic
acid, styrene sulfonic acid, allyl sulfonic acid, vinyl phosphonic
acid and 2-(meth)acryloyloxyethyl phosphate, and alkaline metal
salts and alkaline earth metal salts, ammonium salts, and alkyl
amine salts thereof, dialkyl amino alkyl(meth)acrylates, such as
N,N-dimethylaminoethyl(meth)acrylate and
N,N-dimethylaminopropyl(meth)acrylate, and quaternary compounds
thereof (for example, a reaction product produced with alkylhalide,
and a reaction product produced with dialkyl sulfuric acid);
dialkyl amino hydroxyalkyl(meth)acrylates, and quaternary compounds
thereof; N-alkyl vinyl pyridine halide;
hydroxyalkyl(meth)acrylates, such as hydroxymethyl (meth)acrylate,
2-hydroxyethyl(meth)acrylate, and 2-hydroxypropyl (meth)acrylate;
acrylamide, methacrylamide, N-ethyl (meth)acrylamide,
N-propyl(meth)acrylamide, N-isopropyl(meth)acrylamide, N,N-dimethyl
(meth)acrylamide, 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl
(meth)acrylate, methoxypolyethylene glycol (meth)acrylate,
polyethylene glycol mono(meth)acrylate, vinylpyridine,
N-vinylpyrrolidone, N-acryloyl piperidine, and N-acryloyl
pyrrolidine; vinyl acetate; and alkyl (meth)acrylates, such as
methyl (meth)acrylate, and ethyl (meth)acrylate. These monomers may
be used individually, or in combination.
In certain embodiments, the present invention relates to a
crosslinked gel, comprising a hydrophobic polymer; and a compound
represented by 1 or 2 and any of their respective attendant
definitions.
In certain embodiments, the present invention relates to a
crosslinked gel as defined above, wherein said hydrophobic polymer
comprises an alkyl acrylate, alkyl alkylacrylate, alkyl acrylamide,
or alkyl alkylacrylamide.
In certain embodiments, the present invention relates to a
crosslinked gel as defined above, wherein said hydrophobic polymer
comprises an alkyl methacrylate.
In certain embodiments, the present invention relates to a
crosslinked gel as defined above, wherein said hydrophobic polymer
comprises methyl methacrylate, ethyl methacrylate, n-butyl
methacrylate, or tert-butyl methacrylate.
In certain embodiments, the present invention relates to a
crosslinked hydrogel, comprising a hydrophilic polymer; and a
compound represented by 1 or 2 and any of their respective
attendant definitions.
In certain embodiments, the present invention relates to a
crosslinked hydrogel as defined above, wherein said hydrophilic
polymer comprises an acrylic acid, acrylate, or acrylamide.
In certain embodiments, the present invention relates to a
crosslinked hydrogel as defined above, wherein said hydrophilic
polymer comprises acrylic acid, 2-hydroxyethyl acrylate,
oligo(ethylene glycol) 2-methacrylate, acrylamide,
N,N-dimethylacrylamide, or
N-(tris(hydroxymethyl)methyl)acrylamide.
In certain embodiments, the present invention relates to a
crosslinked hydrogel as defined above, wherein said hydrophilic
polymer consists of a first acrylamide and a second acrylamide.
In certain embodiments, the present invention relates to a
crosslinked hydrogel as defined above, wherein said first
acrylamide is acrylamide or N,N-dimethylacrylamide.
In certain embodiments, the present invention relates to a
crosslinked hydrogel as defined above, wherein said second
acrylamide is N-(tris(hydroxymethyl)methyl)acrylamide.
In certain embodiments, the present invention relates to a
crosslinked hydrogel as defined above, wherein said first
acrylamide is acrylamide or N,N-dimethylacrylamide; and said second
acrylamide is N-(tris(hydroxymethyl)methyl)acrylamide.
In certain embodiments, the present invention relates to a
crosslinked hydrogel as defined above, wherein said hydrophilic
polymer consists of an acrylamide and an acrylate.
In certain embodiments, the present invention relates to a
crosslinked hydrogel as defined above, wherein said acrylamide is
acrylamide or N,N-dimethylacrylamide.
In certain embodiments, the present invention relates to a
crosslinked hydrogel as defined above, wherein said acrylate is
acrylic acid, 2-hydroxyethyl acrylate, or oligo(ethylene glycol)
2-methacrylate.
In certain embodiments, the present invention relates to a
crosslinked hydrogel as defined above, wherein said acrylamide is
acrylamide or N,N-dimethylacrylamide; and said acrylate is acrylic
acid, 2-hydroxyethyl acrylate, or oligo(ethylene glycol)
2-methacrylate.
In certain embodiments, the present invention relates to a
crosslinked hydrogel as defined above, wherein said hydrophilic
polymer consists of a first acrylate and a second acrylate.
In certain embodiments, the present invention relates to a
crosslinked hydrogel as defined above, wherein said first acrylate
is acrylic acid, 2-hydroxyethyl acrylate, or oligo(ethylene glycol)
2-methacrylate.
In certain embodiments, the present invention relates to a
crosslinked hydrogel as defined above, wherein said first acrylate
is acrylic acid, 2-hydroxyethyl acrylate, or oligo(ethylene glycol)
2-methacrylate; and said second acrylate is acrylic acid,
2-hydroxyethyl acrylate, or oligo(ethylene glycol)
2-methacrylate.
Methods of the Invention
The polymerization methods of the present invention may be
practiced in water, organic solvents, or a mixture of both. The
concentration of the unsaturated monomer in the solution
(hereinafter referred to as the monomer solution) is exemplified in
a non-limiting manner within this description as preferably but not
exclusively including a range of from 20 weight percent to 65
weight percent, more preferably from 25 weight percent to 60 weight
percent, most preferably from 30 weight percent to 45 weight
percent.
As noted above, it is also possible to use water and an organic
solvent soluble in water together as a solvent for the monomer
solution. Examples of suitable organic solvents are methyl alcohol,
ethyl alcohol, acetone, dimethyl sulfoxide, ethylene glycol
monomethyl ether, glycerin, (poly)ethylene glycol, (poly)propylene
glycol, and alkylene carbonate. These organic solvents may be used
individually, or in combination.
Finally, also as noted above, a pure organic solvent may be used
for the monomer solution.
The polymerization method is not particularly limited, and various
methods can be used. Examples include radical polymerization using
a radical polymerization initiator, irradiation-induced
polymerization, electron radiation-induced polymerization, and
ultraviolet-induced polymerization using a photosensitizer. Among
these methods, radical polymerization is preferred.
As for the radical polymerization step, there are various
polymerization methods, such as aqueous solution polymerization,
cast polymerization which is performed within a mold, thin-layer
polymerization which is performed on a belt conveyer,
polymerization which is performed while making generated hydrogel
polymer into small pieces, reversed-phase suspension
polymerization, reversed-phase emulsion polymerization,
precipitation polymerization, and bulk polymerization. Among these
polymerization methods, the aqueous solution polymerization which
polymerizes the unsaturated monomer in the form of aqueous solution
is more preferred because the polymerization temperature can be
easily controlled. The aqueous solution polymerization of the
unsaturated monomer may be performed either continuously or
batch-wise, or may be performed under suction, pressure, or
atmospheric pressure. Generally, it is preferred to dissolve or
disperse a radical polymerization initiator in an monomer solution
in advance. Examples of the radical polymerization initiator
include: peroxides, such as ammonium persulfate, potassium
persulfate, sodium persulfate, hydrogen peroxide, benzoyl peroxide,
cumene hydroperoxide, and di-t-butyl peroxide; redox initiators
formed by combining the above-mentioned peroxides and reducing
agents, such as sulfite, bisulfite, thiosulfate, formamidine
sulfinic acid, and ascorbic acid; acrylic acid salts of
azo-compound containing an amino group represented by general
formula (1) or (2) above; and azo polymerization initiators, such
as hydrochlorides of the azo-compound containing an amino group.
These radical polymerization initiators may be used individually,
or in combination. The amount of the radical polymerization
initiator with respect to the unsaturated monomer is varied
depending on the combination of the unsaturated monomer and the
radical polymerization initiator. However, the amount of the
radical polymerization initiator to be used is within a range of
preferably from 0.0005 weight parts to 5 weight parts, more
preferably from 0.005 weight parts to 2.5 weight parts, based on
100 parts by weight of the unsaturated monomer. If the amount of
the radical polymerization initiator is less than 0.0005 weight
parts, the amount of unreacted unsaturated monomers increases,
causing an unfavorable increase of the residual monomer content in
the resulting water-absorbent resin. Although the temperature at
the initiation of polymerization varies depending on the type of a
radical polymerization initiator used, it is preferably within a
range of from 30.degree. C. to 120.degree. C., more preferably from
40.degree. C. to 80.degree. C.
In certain embodiments, the present invention relates to a method
of preparing a polymer comprising a monomer represented by 1 and
the attendant definitions, comprising reacting a monomer
represented by 1 and the attendant definitions with a second
monomer in the presence of an initiator.
In certain embodiments, the present invention relates to a method
of preparing a polymer comprising a monomer represented by 2 and
the attendant definitions, comprising reacting a monomer
represented by 2 and the attendant definitions with a second
monomer in the presence of an initiator.
In certain embodiments, the present invention relates to a method
of preparing a crosslinked gel comprising a monomer represented by
1 or 2 and the attendant definitions, comprising reacting a monomer
represented by 1 or 2 and the attendant definitions with a
hydrophobic monomer in the presence of an initiator.
In certain embodiments, the present invention relates to a method
of preparing a crosslinked gel comprising a monomer represented by
1 or 2 and the attendant definitions, comprising reacting a monomer
represented by 1 or 2 and the attendant definitions with a
hydrophilic monomer in the presence of an initiator.
EXEMPLIFICATION
The invention now being generally described, it will be more
readily understood by reference to the following examples, which
are included merely for purposes of illustration of certain aspects
and embodiments of the present invention, and are not intended to
limit the invention.
Example 1
Synthesis of N-methacryloylhydroxylamine (MHA)
MHA was synthesized by reacting methyl methacrylate (MMA) with
hydroxylamine in a basic aqueous solution. In a 700 mL beaker,
hydroxylamine hydrochloride (70 g) was added, which was dissolved
in 150 g of sterile water. The aqueous solution thus obtained was
cooled to 0.degree. C., to which MMA (100 g) was added. In another
beaker, sodium hydroxide (80 g) was dissolved in sterile water (140
g). After cooling to 0.degree. C., this basic aqueous solution was
dropwise added to the first beaker with vigorous stirring. At this
stage, the formation of MHA was confirmed by testing the reaction
mixture with an acidic aqueous solution of ferric chloride (The
deep-red color of the complex formed between MHA and FeCl.sub.3
appeared instantaneously). After the reaction lasted 3 h at
0.degree. C., the system was concentrated by distillation under
reduced pressure and the residue was extracted with ether (200 mL)
for six times. The ether phase was concentrated by evaporation and
a solid product was obtained by crystallization from a mixture of
ether and hexane. The 1H NMR spectrum of this crystal is consistent
with the molecular structure of MHA (in DMSO-D.sub.6 : --NHOH,
10.70 and 8.79 ppm; C.dbd.CH.sub.2, 5.28 and 5.57 ppm; --CH.sub.3,
1.82 ppm) and no impurity was detected.
Example 2
Synthesis of a Crosslinker: MHA-DIH
##STR21##
MHA-DIH is the adduct of one 1,6-diisocyanatohexane (DIH) molecule
and two MHA molecules, which was prepared by reacting DIH with MHA
in THF at room temperature. A well-dried 250 mL round-bottom flask
containing a magnetic stirring bar was protected with nitrogen, to
which MHA (11.1 g, 0.11 mol) was first added and this was followed
by the addition of CaH.sub.2 -dried THF (40 g). After MHA dissolved
completely, DIH (8.3 mL, 0.05 mol) was diluted with THF (16 g) and
dropwise added with a dried syringe over 15 min. The reaction was
allowed to last 24 h at room temperature with stirring. Then, the
reaction system was concentrated by evaporating and put into the
refrigerator for crystallization. The white crystal crosslinker
MHA-DIH was obtained by filtration, washed with THF three times,
and vacuum-dried overnight (Yield=46% based on the feed amount of
DIH). Its very high purity was conformed by 1H NMR measurement (in
DMF-d.sub.7): 11.47 ppm, 2H, O.dbd.C--NHO; 7.58 ppm, 2H,
O.dbd.C--NH--C; 5.47 and 5.80 ppm, 4H, CH.sub.2.dbd.; 3.14 ppm, 4H,
--NHCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 NH--;
1.92 ppm, 6H, --CH.sub.3 ; 1.50 ppm, 4H, --NHCH.sub.2 CH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 NH--; 1.33 ppm, 4H, NHCH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 NH--.
Example 3
Synthesis of a Crosslinker: MHA-DIB
##STR22##
MHA-DIB is the adduct of one 1,4-diisocyanatobutane (DIB) molecule
and two MHA molecules, which was prepared by reacting DIB with MHA
in THF at room temperature. As described for the preparation of
MHA-DIH, a similar synthetic procedure was also applied to MHA-DIB.
A white crystal product was obtained with a yield of 39% based on
the feed amount of DIB. Similar to that of MHA-DIH, its NMR
spectrum is completely consistent with its molecular structure (in
DMF-d.sub.7): 11.48 ppm, 2H, O.dbd.C--NHO; 7.60 ppm, 2H,
O.dbd.C--NH--C; 5.48 and 5.81 ppm, 4H, CH.sub.2.dbd.; 3.16 ppm, 4H,
NHCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 NH; 1.93 ppm, 6H, --CH.sub.3
; 1.55 ppm, 4H, --NHCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 NH--.
Example 4
Preparation of DMA Homopolymer Beads Using MHA-DIH as the
Crosslinker
A 500 mL open-mouth jacketed flask was equipped with a mixer, a
thermometer and a temperature controller, to which 150 mL of
mineral oil and 0.12 g of sorbitan sesquioleate (SSO) were
sequentially added. This system was heated to 60.degree. C. by
circulating water with stirring (350 rpm), and used as the
continuing oil phase.
Simultaneously, the water phase was prepared in a small beaker as
follows. Sodium chloride (23.2 g) and sodium acetate (11.0 g) were
first dissolved in distilled water (81.6 mL). Then, this aqueous
solution was mixed with glycerol (163 mL) with magnetic stirring.
Finally, the pH value of this mixture was regulated to 6.0 by
adding acetic acid.
The buffer solution (pH=6.25 mL) was used to dissolve DMA (5.0 g).
To this solution, the crosslinker MHA-DIH (25 w % DMF solution, 1.8
g) was dropwise added with stirring. This mixture was heated to
60.degree. C. in an oil bath. As soon as the initiator APS (0.15 g)
was added, this water phase was transferred into the oil phase with
fast stirring (650 rpm), and TMEDA (0.4 mL) was added immediately
to accelerate the reaction. After the polymerization lasted 30 min,
the mixture was rinsed into about 120 mL of water (pH=3.0) to
separate the beads. The beads in water phase were washed with water
(pH=3) for more than five times, then, immersed in a buffer (pH=2)
and stored in the refrigerator (4.degree. C.). This kind of beads
in the buffer solution (pH=7.4) degraded completely within 5 days
at 37.degree. C. As shown in Table 1, by using different monomers
and/or crosslinker, several kinds of homopolymer beads were
prepared.
TABLE 1 Preparation of homo- and co-polymer beads. Monomer 1
Monomer 2 Degradation time Degradation time at (%).sup.a (%).sup.a
Crosslinker (%).sup.b at pH = 7.4.sup.c pH = 2.sup.d DMA 100
MHA-DIH 9 5 days No degradation after 2 months TS 100 MHA-DIH 9 1.5
days No degradation after 2 months HEA 100 MHA-DIH 9 >16 days No
degradation after 2 months DMA 80 TS 20 MHA-DIH 9 3 days No
degradation after 2 months DMA 50 TS 50 MHA-DIH 9 1.5 days No
degradation after 2 months DMA 80 HEA 20 MHA-DIH 9 3.5 days No
degradation after 2 months DMA 50 HEA 50 MHA-DIH 9 7 days No
degradation after 2 months DMA 100 MHA-DIB 9 2.5 days No
degradation after 2 months TS 100 MHA-DIB 9 1 day No degradation
after 2 months HEA 100 MHA-DIB 9 >5 days No degradation after 2
months DMA 80 TS 20 MHA-DIB 9 1.5 days No degradation after 2
months DMA 50 TS 50 MHA-DIB 9 2.5 days No degradation after 2
months DMA 50 HEA 50 MHA-DIB 9 3 days No degradation after 2 months
.sup.a TS: [tris(hydroxymethyl)]methyl acrylate; HEA: 2-hydroxyethl
methacrylate; DMA: N,N-dimethylacrylamide. .sup.b Compared to the
total amount of the monomer(s), 9 wt % of the crosslinker was used.
.sup.c At 37 C. .sup.d At 5 C.
Example 5
Preparation of DMA-TS Copolymer Beads
The oil phase preparation was carried out in the same way as used
in Example 5. However, instead of only one monomer, both TS and DMA
were included in the water phase. 1.0 g of TS was first dissolved
in the buffer solution (25 g, pH=6; see Example 5) at 45.degree. C.
Then, 4.0 g of DMA and a DMF solution of the crosslinker MHA-DIB
(25 wt %, 1.8 g) were dropwise added with stirring. This system was
heated to 60.degree. C. in an oil bath. Upon the addition of 0.15 g
of APS, this mixture was poured into the oil phase and the
accelerator TMEDA (0.40 mL dissolved in 2 mL mineral oil) was added
immediately. About 30 min later, the beads thus obtained were
purified in the way similar to that used in Example 5. This kind of
beads in the buffer solution (pH=7.4) degraded completely within
1.5 days at 37.degree. C. As shown in Table 1, by using different
monomers and/or crosslinker, several kinds of copolymer beads were
prepared.
Incorporation by Reference
All of the patents and publications cited herein are hereby
incorporated by reference.
Equivalents
Those skilled in the art will recognize, or be able to ascertain
using no more than routine experimentation, many equivalents to the
specific embodiments of the invention described herein. Such
equivalents are intended to be encompassed by the following
claims.
* * * * *